NM_001100.4(ACTA1):c.986_989dup (p.Lys330fs) AND Actin accumulation myopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 5, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002828164.3

Allele description [Variation Report for NM_001100.4(ACTA1):c.986_989dup (p.Lys330fs)]

NM_001100.4(ACTA1):c.986_989dup (p.Lys330fs)

Gene:

ACTA1:actin alpha 1, skeletal muscle [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1q42.13

Genomic location:

Preferred name:

NM_001100.4(ACTA1):c.986_989dup (p.Lys330fs)

HGVS:

NC_000001.11:g.229431723_229431726dup
NG_006672.1:g.7372_7375dup
NG_093759.1:g.728_731dup
NG_093760.1:g.108_111dup
NM_001100.4:c.986_989dupMANE SELECT
NP_001091.1:p.Lys330Asnfs
NP_001091.1:p.Lys330fs
LRG_429t1:c.985_988dup
LRG_429:g.7372_7375dup
LRG_429p1:p.Lys330Asnfs
NC_000001.10:g.229567468_229567469insTTGA
NC_000001.10:g.229567470_229567473dup
NM_001100.3:c.985_988dup

Protein change:

K330fs

Molecular consequence:

NM_001100.4:c.986_989dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Actin accumulation myopathy (CMYO2A)
Synonyms:: Nemaline myopathy caused by mutation in the alpha-actin gene; CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT; Myopathy, actin, congenital, with cores; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008070; MedGen: C3711389; OMIM: 161800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003204029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17187373, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003204029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 5, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nemaline myopathy caused by absence of alpha-skeletal muscle actin.

Nowak KJ, Sewry CA, Navarro C, Squier W, Reina C, Ricoy JR, Jayawant SS, Childs AM, Dobbie JA, Appleton RE, Mountford RC, Walker KR, Clement S, Barois A, Muntoni F, Romero NB, Laing NG.

Ann Neurol. 2007 Feb;61(2):175-84.

PubMed [citation]

PMID:: 17187373

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003204029.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the C-terminus of the ACTA1 protein. Other variant(s) that disrupt this region (p.Tyr364*) have been observed in individuals with ACTA1-related conditions (PMID: 17187373). This suggests that this may be a clinically significant region of the protein. This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ACTA1 gene (p.Lys330Asnfs*72). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the ACTA1 protein and extend the protein by 23 additional amino acid residues.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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